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Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes

Authors
  • Delépine, Chloé
  • Meziane, Hamid
  • Nectoux, Juliette
  • Opitz, Matthieu
  • Smith, Amos B.
  • Ballatore, Carlo
  • Saillour, Yoann
  • Bennaceur-Griscelli, Annelise
  • Chang, Qiang
  • Williams, Emily Cunningham
  • Dahan, Maxime
  • Duboin, Aurélien
  • Pierre Billuart
  • Herault, Yann
  • Thierry Bienvenu
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Publication Date
Jul 25, 2016
Volume
25
Issue
1
Pages
57–146
Identifiers
DOI: 10.1093/hmg/ddv464
PMID: 26604147
PMCID: PMC4690499
Source
USPC - SET - SVS
License
Green

Abstract

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.

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